This invention relates to Acquired Immunodeficiency Syndrome (AIDS) and, more specifically, to immunogenic compositions for use in preventing and treating AIDS.
More than 30 million people world wide are now infected with the human immunodeficiency virus (HIV), the virus responsible for AIDS. About 90% of HIV infected individuals live in developing countries, including sub-Saharan Africa and parts of South-East Asia, although the HIV epidemic is rapidly spreading throughout the world. Anti-viral therapeutic drugs that reduce viral burden and slow the progression to AIDS have recently become available. However, these drugs are prohibitively expensive for use in developing nations. Thus, there remains an urgent need to develop effective preventative and therapeutic vaccines to curtail the global AIDS epidemic.
To date, HIV has proven a difficult target for effective vaccine development. Because of the propensity of HIV to rapidly mutate, there are now numerous strains predominating in different parts of the world whose epitopes differ. Additionally, in a particular infected individual, an HIV virus can escape from the control of the host immune system by developing mutations in an epitope. There remains a need to develop improved HIV vaccines that stimulate the immune system to recognize a broad spectrum of conserved epitopes, including epitopes from the p24 core antigen.
During the 1990""s, more than 30 different candidate HIV-1 vaccines entered human clinical trials. These vaccines elicit various humoral and cellular immune responses, which differ in type and strength depending on the particular vaccine components. There remains a need to develop HIV vaccine compositions that strongly elicit the particular immune responses correlated with protection against HIV infection.
The nature of protective HIV immune responses has been addressed through studies of individuals who have remained uninfected despite repeated exposure to HIV, or who have been infected with HIV for many years without developing AIDS. These studies have shown that immune responses of the T helper 1 (Th1) type correlate well with protection against HIV infection and subsequent disease progression. Besides antigen-specific Th1 responses, CD8+ cytotoxic T cell responses are considered important in preventing initial HIV infection and disease progression. During an effective anti-viral immune response, activated CD8+ T cells directly kill virus-infected cells and secrete cytokines with antiviral activity.
The xcex2-chemokine system also appears to be important in protection against initial HIV infection and disease progression. Infection of immune cells by most primary isolates of HIV requires interaction of the virus with CCR5, whose normal biological role is as the principal receptor for the xcex2-chemokines RANTES, MIP-1xcex1 and MIP-xcex2. Genetic polymorphisms resulting in decreased expression of the CCR5 receptor have been shown to provide resistance to HIV infection. Additionally, a significant correlation between xcex2-chemokine levels and resistance to HIV infection, both in exposed individuals and in cultured cells, has been demonstrated. It has been suggested that xcex2-chemokines may block HIV infectivity by several mechanisms, including competing with or interfering with HIV binding to CCR5, and downregulating surface CCR5.
Because of the importance of xcex2-chemokines in preventing initial HIV infection and disease progression, an effective HIV immunogenic composition should induce high levels of xcex2-chemokine production, both prior to infection and in response to infectious virus. However, HIV immunogenic compositions capable of inducing high levels of xcex2-chemokine production have not been described. In particular, immunogenic compositions which stimulate high levels of xcex2-chemokine production, induce HIV-specific Th1 cellular and humoral immune responses, and induce HIV-specific cytotoxic activity, have not been described.
Compositions that elicit certain types of HIV-specific immune responses may not elicit other important protective responses. For example, Deml et al., Clin. Chem. Lab. Med. 37:199-204 (1999), describes a vaccine containing an HIV-1 gp160 envelope antigen, an immunostimulatory DNA sequence and alum adjuvant, which, despite inducing an antigen-specific Th1-type cytokine response, was incapable of inducing an antigen-specific cytotoxic T lymphocyte response. Furthermore, a vaccine containing only envelope antigens would not be expected to induce an immune response against the more highly conserved core proteins of HIV.
Thus, there exists a need for immunogenic compositions and methods that will prevent HIV infection as well as slow progression to AIDS in infected individuals. Ideally, such compositions and methods will elicit potent Th1 cellular and humoral immune responses specific for conserved HIV epitopes, elicit HIV-specific cytotoxic T lymphocyte activity, and stimulate production of high levels of xcex2-chemokines. Such vaccines could be used to prevent maternal transmission of HIV, for vaccination of newborns, children and high-risk individuals, and for vaccination of infected individuals. Such vaccines could also be used in combination with other HIV therapies, including protease inhibitors. The present invention satisfies this need and provides related advantages as well.
The invention provides immunogenic compositions which enhance xcex2-chemokine levels in a mammal. The immunogenic compositions contain an HIV antigen, an isolated nucleic acid molecule containing an immunostimulatory sequence (ISS) and an adjuvant. The HIV antigen can be a whole-killed HIV virus devoid of outer envelope protein gp120. Alternatively, the HIV antigen can be a whole-killed HIV virus, or a p24 antigen.
In the immunogenic compositions of the invention, the isolated nucleic acid molecule containing an ISS can be an oligodeoxynucleotide. The isolated nucleic acid molecule containing an ISS can contain two or more CpG sequences. Exemplary ISS-containing nucleic acid molecules contain the motif 5xe2x80x2-Cytosine, Guanine, Pyrimidine, Pyrimidine-3xe2x80x2. The isolated nucleic acid molecule can contain a phosphorothioate backbone. The isolated nucleic acid molecule can be conjugated to the HIV antigen.
In the immunogenic compositions of the invention, the adjuvant can be suitable for administration to a human. An exemplary adjuvant is Incomplete Freund""s Adjuvant.
The immunogenic compositions of the invention can further enhance HIV-specific IgG2b antibody production in a mammal. The immunogenic compositions of the invention can also enhance an HIV-specific cytotoxic T lymphocyte response in a mammal.
Also provided are kits, which contain an HIV antigen, an isolated nucleic acid molecule containing an immunostimulatory sequence (ISS) and an adjuvant. The components of the kits, when combined, produce the immunogenic compositions of the invention.
The invention also provides methods of making the immunogenic compositions, by combining an HIV antigen, an isolated nucleic acid molecule containing an immunostimulatory sequence (ISS) and an adjuvant. The components can be combined ex vivo or in vivo to arrive at the immunogenic compositions.
The invention also provides a method of immunizing a mammal, by enhancing xcex2-chemokine production in the mammal by administering to the mammal an immunogenic composition containing an HIV antigen, an isolated nucleic acid molecule containing an immunostimulatory sequence (ISS) and an adjuvant. Also provided is a method of inhibiting AIDS, by enhancing xcex2-chemokine production in the mammal by administering to the mammal an immunogenic composition containing an HIV antigen, an isolated nucleic acid molecule containing an immunostimulatory sequence (ISS) and an adjuvant. In the methods of the invention, the mammal can be a primate, such as a human, or a rodent. In certain embodiments of the method, the primate is a pregnant mother or an infant. A human can be HIV seronegative or HIV seropositive. The immunogenic compositions can advantageously be administered to the mammal two or more times.